ORIGINAL RESEARCH ARTICLE
Impact of Diabetes on Outcomes of Sorafenib Therapy
for Hepatocellular Carcinoma
Giovan Giuseppe Di Costanzo1&Raffaella Tortora1&Filomena Morisco2&
Luigi Addario1&Maria Guarino2&Gabriella Cordone1&Luigia Falco1&
Nicola Caporaso2
Published online: 9 August 2016
# Springer International Publishing Switzerland 2016
Abstract
Background Patients with diabetes are at increased risk of developing hepatocellular carcinoma (HCC) and have a poorer prognosis as compared to non-diabetics when HCC occurs. Diabetics with non-HCC cancers are at higher risk of toxicity related to systemic therapy, but data on HCC are lacking.
Objective The aim of this study was to evaluate safety and effectiveness of sorafenib in HCC patients according to the presence/absence of diabetes.
Patients and Methods From October 2008 to June 2014, 313 patients with HCC treated with sorafenib were enrolled. The patients were staged according to the BCLC system. Treatment response was evaluated according to the mRECIST criteria. The main evaluated outcomes were the overall survival and the safety in the two groups.
Results Patients were divided in two groups: 80 diabetics (DIAB) and 233 nondiabetics (nDIAB). The median treatment duration was 4 months in DIAB and 3 months in nDIAB. Main adverse events occurred with comparable frequency in both groups, with the exception of rash, that was more fre-quent among DIAB than in nDIAB: 27.5 % vs 17.6 % (P = .047). The median overall survival was 9 months in nDIAB and 10 months in DIAB group (P = .535). Median time-to-progression (TTP) was longer the in DIAB than the nDIAB group (P = .038).
Conclusions Sorafenib was as safe as effective in DIAB and in nDIAB patients. The longer TTP observed among DIAB than in nDIAB patients might suggest a better anticancer ef-fect of sorafenib in patients with diabetes.
Key Points
Sorafenib in diabetics was safe and the longer TTP observed in diabetics might suggest a better anticancer effect of sorafenib in patients with diabetes.
The better TTP in patients treated with oral therapy as compared to those receiving insulin is interesting and concordant with previous studies on different cancers.
Abbreviations
HCC Hepatocellular carcinoma
HCV Hepatitis C virus
HBV Hepatitis B virus
EASL European Association for the study of the liver BCLC Barcelona clinic liver cancer
ECOG Eastern cooperative oncology group
PS Performance status
AFP Alpha fetoprotein
US Ultrasound
CT Computed tomography
MRI Magnetic resonance imaging
OS Overall survival
TTP Time-to-progression
mRECIST Modified Response Evaluation Criteria in Solid Tumours for hepatocellular carcinoma
CR Complete response
PR Partial response
* Giovan Giuseppe Di Costanzo
ggdicostanzo@libero.it; dicostanzogg@gmail.com
1
Department of Transplantation - Liver Unit, Cardarelli Hospital, Via A. Cardarelli 9, 80131 Naples, Italy
2 Department of Clinical Medicine and Surgery - Gastroenterology Unit, University of NaplesBFederico II^, Naples, Italy
SD Stable disease
PD Progressive disease
DIAB Diabetics
nDIAB Nondiabetics
HFS Hand foot syndrome
TACE Transarterial chemoembolization
1 Introduction
Hepatocellular carcinoma (HCC) is a leading cause of death for cancer worldwide [1]. In Western countries, HCC occurs in most of cases in patients with cirrhosis, that is, therefore, a preneoplastic state, and is the main cause of death among cirrhotics [2,3]. Hepatitis C (HCV) and B (HBV) viral infec-tions and alcohol consumption are the main etiological agents. In the last years, nonalcoholic fatty liver disease and steatohepatitis are becoming increasingly recognized causes of cirrhosis and HCC [4]. Metabolic syndrome, mainly obesity and diabetes, is strictly related to the presence of liver steatosis and steatohepatitis [5]. Patients with obesity and type 2 diabetes are at increased risk of developing HCC [6, 7]. A longer duration of diabetes is related to a higher rate of HCC development [8,9], and diabetes may worsen the outcomes of patients with cirrhosis and HCC [10–13]. Furthermore, im-paired carbohydrate metabolism is more frequently observed in cirrhosis than in the general population and about a third of these patients have type 2 diabetes [14].
In spite of more extensive use of surveillance and liver imaging in patients with cirrhosis, a substantial proportion of HCC are diagnosed in intermediate and advanced stage and only 30 % of patients can be treated with potentially curative therapies. Moreover, over time a considerable percentage of early HCC patients progresses to the advanced stage [15]. Therefore, many patients with HCC necessitate systemic treat-ment, and sorafenib (Nexavar©, Bayer Health Care, Leverkusen, Germany) is the only drug approved worldwide for HCC advanced stage patients who are not candidates to curative treatments [16]. However, systemic therapy in pa-tients with diabetes might be challenging. Papa-tients with diabe-tes and non-HCC cancers are at higher risk of toxicity related to systemic treatment and often are treated with less aggres-sive therapies as compared to patients without diabetes [17,
18]. Data regarding HCC patients are lacking and only a small study on patients with metastatic renal cell carcinoma or ad-vanced HCC showed that sorafenib treatment in diabetic pa-tients was safe [19]. Due to the high prevalence and the role of diabetes in HCC these data are necessary and clinically rele-vant. Therefore, the aim of this field-practice study was to evaluate safety and effectiveness of sorafenib treatment in a large cohort of HCC patients according to the presence or absence of diabetes.
2 Patients and Methods
2.1 PatientsFrom October 2008 to June 2014, all consecutive patients with unresectable HCC who were treated with sorafenib at-tending the Liver Unit of Cardarelli Hospital were included in this single centre prospective observational study. The diag-nosis of HCC was performed according to the European Association for the Study of the Liver (EASL) criteria [20]. At the time of starting the treatment with sorafenib, the tumor stage was assessed following the Barcelona Clinic Liver Cancer (BCLC) staging system [21]. Patients were treated with sorafenib in case of HCC untreatable with surgery or locoregional therapy, ECOG (Eastern Cooperative Oncology Group) performance status (PS) 0–1, and Child-Pugh score ≤ 7. Starting dose of sorafenib was 800 mg/day, except for pa-tients with bilirubin >2 mg/dL or ascites in whom the dose was reduced to 400 mg/day.
The diagnosis of diabetes was performed when fasting blood glucose was greater than or equal to 126 mg/dl, accord-ing to the American Diabetes Association guidelines 2015 [22].
2.2 Assessment Schedule
At baseline, all necessary patient characteristics were evaluat-ed: age, sex, height, weight, clinical information, biochemical parameters, serum alpha-fetoprotein (AFP), upper gastrointes-tinal endoscopy, abdominal Doppler ultrasound (US), chest computed tomography (CT), and abdominal contrast-enhanced CT or magnetic resonance imaging (MRI). In pa-tients with suspected bone metastasis, a bone scintigraphy was performed. The treatment duration was calculated by sum-ming the days of drug intake, excluding the intervals of tem-porary discontinuation of sorafenib.
Once a month patients underwent to clinical evaluation, biochemical tests, AFP, abdominal US, pill-count for the eval-uation of compliance to treatment, and record of adverse events according to definitions from the National Cancer Institute's Common Toxicity Criteria version 3.0 (http://ctep. info.nih.gov/CTC3/ctc ind term.html), using a pre-planned questionnaire. For a better management of patients, a call cen-tre was available every day to patients for consulting a doctor. To evaluate radiological response to treatment, CT or MRI scans were performed every 3 months and in any case of suspected progression.
2.3 Outcomes and Assessments
The main evaluated outcomes were the overall survival (OS) and the safety in the two groups.
The OS was measured from the date of starting sorafenib until the date of death or the last visit. The safety was assessed evaluating the occurrence and the grade of sorafenib adverse events.
Secondary outcomes were the 3-month radiological re-sponse to sorafenib and the time-to-progression (TTP). The radiological response to sorafenib was evaluated according to the modified Response Evaluation Criteria in Solid Tumours for Hepatocellular Carcinoma (mRECIST) criteria [23]. Response to therapy was classified as complete response (CR), partial response (PR), stable disease (SD), or progres-sive disease (PD). The disease-control rate (DCR) was defined as the percentage of patients who had a best response rating of complete response, partial response, or stable disease.
The TTP was measured from the starting treatment data until the clinical or radiological evidence of disease progres-sion or last follow-up.
2.4 Statistical Analysis
A two-tailed p-value < 0.05 was considered to indicate statis-tical significance. Categorical data were compared using Fisher’s exact test. Continuous variables were shown as me-dian and compared with the non-parametric Mann–Whitney test. Time-to-event data was visualized using Kaplan–Meier curves and compared by the log-rank test. All statistical anal-yses were performed with software package SPSS for Mac (Rel SPSS 21.0; IBM Corporation, Armonk, NY, USA, 2012).
3 Results
Three hundred thirteen patients with HCC treated with soraf-enib were included in the study. Patients were divided in two groups according to the presence of diabetes: 80 diabetics
Table 1 Baseline characteristics of diabetic and nondiabetic patients Characteristics DIAB n = 80 nDIAB n = 233 P Males 56 (70 %) 175 (75 %) .379
Median age (range) 68 (41–84) 67 (35–90) .805
HCV infection 54 (67.5 %) 152 (65.5 %) .786
HBV infection 9 (11.3 %) 42 (18.0 %) .157
Alcohol 8 (10.0 %) 15 (6.4 %) .292
NAFLD 6 (7.5 %) 11 (4.7 %) .344
Other aetiologies 3 (3.7 %) 13 (5.6 %) .120
Median BMI, (range) 25 (18–45) 25 (18–35) .815
Child score 5 45 (56.3 %) 123 (52.8 %) .145 Child score 6 31 (38.8 %) 80 (34.3 %) Child score 7 4 (5 %) 30 (12.9 %) Ascites 11 (13.8 %) 35 (15 %) .856 Bilirubin≤ 2 mg/dL 76 (95.0 %) 208 (89.3 %) .179 Albumin≥ 3.5 g/dL 57 (71.2 %) 174 (74.7 %) .555 BCLC B 18 (22.5 %) 55 (23.6 %) .880 BCLC C 62 (77.5 %) 178 (76.4 %) Portal thrombosis 41 (51.3 %) 117 (50.2 %) .897 Extrahepatic metastasis 28 (35.0 %) 76 (32.7 %) .783 Median AFP ng/mL (range) 313 (2–433,250) 290 (1–741,720) .690 Previously treated, n 52 (65.0 %) 153 (65.7 %) 1.00
Liver transplantation 1 (1.3 %) 11 (4.7 %) .772
Surgical resection 3 (3.7 %) 5 (2.1 %)
Local ablation 10 (12.5 %) 25 (10.7 %)
TACE 20 (25.0 %) 47 (20.2 %)
Combined locoregional treatments 18 (22.5 %) 65 (27.9 %) No previous treatment 28 (35.0 %) 80 (34.3 %)
Median treatment duration, months 4 (1–41) 3 (1–56) .178 Starting sorafenib dose 800 mg/d 71 (88.8 %) 205 (88.0 %) 1.00
Median daily dose 673 mg 622 mg .496
Median daily dose≥ 400 mg, n of patients 75 (93.8 %) 203 (87.1 %) .148 Median survival, months, (95%CI) 10 (7.6-12.4) 9 (7.5-10.5) .478
(DIAB) and 233 nondiabetics (nDIAB). No differences in demographics, liver function, and cancer stage between DIAB and nDIAB groups were observed (Table1).
All DIAB patients were affected by type 2 diabetes and the treatment was: exogenous insulin in 57.5 %, oral hypoglyce-mic agents in 28.8 %, acarbose and diet in 13.7 %. After 1–2 cycles of sorafenib, nine (11 %) patients had reduced or
stopped blood glucose-lowering drugs due to the decrease in blood glucose level. One patient experienced severe hypoglycaemia.
The median duration of sorafenib treatment was 4 (range 1–41) months in DIAB and 3 (1–56) months in nDIAB.
Adverse events were observed in 96.3 % and in 94 % of DIAB and nDIAB patients, respectively. Main adverse events (fatigue, hand foot syndrome (HFS), diarrhea, and hyperten-sion) occurred with comparable frequency in both groups (Table2). Rash was the only adverse event more frequent in DIAB as compared to nDIAB: 27.5 % vs 17.6 % (P = .047).
Median sorafenib dose was 621 mg/day (range 55–800) in nDIAB and 673 mg/day (range 81–800) in DIAB group (P = .218). Sorafenib was temporary and permanently discontinued due to adverse events in 23.2 % and 27.2 % in the nDIAB group, and in 21.3 % and 30.4 % in the DIAB group, respectively.
The median overall survival was 9 months (95 % CI, 7.45-10.55) in nDIAB and 10 months (95 % CI, 7.57-12.43) in DIAB group (P = .535) (Fig.1).
Clinical or radiological progression was observed in 107 (45.9 %) patients of the nDIAB group and in 31 (38.8 %) patients of the DIAB group (P = .105). The radiological eval-uation of response after 3 months of therapy was available in 199 (63.6 %) of patients (Table3). The DCR was 71.5 % (103 among 144 patients) and 83.6 % (46 among 55 patients) in the nDIAB and DIAB groups, respectively (P = .10). The proba-bility of disease progression at 6-month and 12-month was 44.0 % and 59.4 % in the nDIAB group, 34.7 % and 44.4 %
Fig. 1 Median overall survival in diabetic and nondiabetic patients
Table 2 Side effects to sorafenib treatment in diabetic and nondiabetic patients
Side effects DIAB Grade 1-2/3-4 nDIAB Grade 1-2/3-4 P Fatigue 48.8 %/3.8 % 45.7 %/3.9 % .973 Anorexia 47.6 %/1.3 % 38.3 %/2.6 % .480 HFS 46.3 %/3.8 % 37.1 %/5.2 % .248 Diarrhea 41.3 %/3.8 % 46.1 %/3.9 % .818 Arterial hypertension 26.3 %/0 % 25.4 %/0.9 % .836 Rash 27.5 %/0 % 15 %/2.6 % .047 Weight loss 22.6 %/0 % 19.8 %/0 % .863 Alopecia 18.9 %/0 % 13.7 %/0 % .682 Pruritus 17.6 %/0 % 11.2 %/0.9 % .372 Abdominal pain 17.5 %/0 % 22.2 %/1.7 % .407 Nausea 15.1 %/2.5 % 14.6 %/0.4 % .427 Jaundice 10.1 %/6.3 % 17.7 %/5.6 % .309 Aftosis 10.1 %/0 % 7.3 %/0.9 % .376 Vomiting 7.6 %/0 % 5.6 %/0.4 % .756 Bleeding 2.5 %/2.5 % 3.9 %/3.3 % .685
in the DIAB group. Cancer progression was observed in 107 among 233 patients and in 31 among 80, in the nDIAB and DIAB groups, respectively. Median TTP was 19 months (95%CI, 2.06-35.94) in the DIAB group and 9 months (95%CI, 6.51-11.49) in the nDIAB group (P = .038) (Fig.2). In the DIAB group, median TTP was 16 months in insulin-treated patients and 27 months in patients insulin-treated with oral hypoglycemic agents.
4 Discussion
This is the first study that evaluated the interaction between diabetes and sorafenib treatment in a large cohort of HCC patients.
Type 2 diabetes increases the risk of HCC occurrence by two to four fold [6,7]. Liver steatosis and steatohepatitis often observed in diabetics may be a cause for it. However, type 2 diabetes may also stimulate cancer development and progres-sion by hyperglicemia and hyperinsulinemia. According to the
Warburg hypothesis, hyperglicemia favours glycolisis that is a main energy producing process in many cancer cells [24]. Hyperinsulinemia is a risk factor for the development of can-cer [25,26]. Insulin produced by pancreatic cells through portal circulation reaches the liver and, therefore, is exposed to very high concentrations of this hormone [27]. Insulin and insulin-like growth factor receptors are expressed on the sur-face of most cancer cells. Insulin receptor is expressed mainly as A isoform. Both receptors when activated may enhance cancer cell proliferation, metastasis, and inhibit apoptosis. In particular, the activation of A isoform insulin receptors may enhance more cell survival and proliferation than glucose up-take [28]. Another mechanism may be the reduced hepatic synthesis of insulin growth factor-binding protein-1, resulting in increased bioavailability of insulin-like growth factor-1 which leads to cellular proliferation promotion and apoptosis inhibition [29].
The risk of cancer occurrence is higher in patients treated with insulin or sulfonylureas, whereas it is reduced with the use of metformin [8,30,31]. Some epidemiologic studies and basic science suggests an association between metformin use and lower cancer risk in diabetic patients, in particular it is associated with lower incidence and mortality for all cancers. Pathophysiological mechanisms of this significant risk have been proposed, but they are still incompletely defined. Metformin has a potential anti-cancer effect by activating adenosine 5′-mono-phosphate-activated protein kinase (AMPK) in addition to alleviating hyperinsulinemia and hy-perglycemia. [32]. Metformin has also a direct effect on CD8+ tumor-infiltrating lymphocytes protecting them from
Table 3 Radiological response at 3 months in diabetic and nondiabetic patients
Radiological response NDIAB DIAB Progression 41 (28.5 %) 9 (16.4 %)
Stable 65 (45.1 %) 26 (47.3 %)
Partial response 33 (22.9 %) 19 (34.5 %) Complete response 5 (3.5 %) 1 (1.8 %)
Fig. 2 Time-to-progression in diabetic and nondiabetic patients
apoptosis and counteracting immune exhaustion [33]. Furthermore, metformin seems to inhibit cancer cell prolifer-ation acting as a negative regulator of mTOR [34].
In patients not treated with sorafenib, some studies have shown that diabetes may worsen the outcomes of HCC pa-tients [10,35].
Tyrosine kinase inhibitors can affect the insulin signalling pathway reducing the mitogenic effect and improving glyce-mic control in diabetics. This last effect was observed in 11 % of our patients. Potential mechanisms related to this effect are shown in Table 4. In a single patient a severe episode of hypoglicemia occurred. These findings suggest that patients with diabetes who are treated with sorafenib should be cau-tiously monitored.
The main aim of the study was to test if systemic treatment was as effective and safe in patients with unresectable HCC and type 2 diabetes as compared to patients without diabetes. Sorafenib therapy in diabetic patients was safe. Adverse events occurred with comparable frequency in DIAB and nDIAB patients, except for skin rash that was observed more often in the DIAB group. Median daily dose was comparable between the DIAB and nDIAB groups. Also temporary or definitive discontinuation of sorafenib due to adverse effects was registered with the same rate in the two groups. Overall survival was similar between DIAB and nDIAB groups.
Among secondary outcomes, 3-month radiological re-sponse evaluation showed a lightly higher rate of DCR in DIAB than in nDIAB patients, but the difference did not reach statistical significance.
Unexpectedly, a longer TTP in the DIAB group as com-pared to the nDIAB group (19 vs 9 months, P = .038) was observed. This finding needs to be evaluated in prospective studies. The TTP was longer in DIAB patients treated with oral hypoglycemic agents as compared to those treated with exogenous insulin (27 vs 16 months). These findings contrast with the results of another study showing a shorter progression-free survival and OS in sorafenib-treated patients taking metformin as compared to insulin-treated patients [38]. Definitive conclusions cannot be drawn due to the low num-ber of patients, although previous studies on other cancer types showed that metformin increased the response to che-motherapy and decreased the occurrence of metastasis [39–42]. Furthermore, in a recent study on metastatic renal
carcinoma, for patients treated with sunitinib, the OS was longer in diabetics taking metformin [43].
In conclusion, sorafenib was as safe as effective in DIAB and in nDIAB patients. The longer TTP observed in DIAB as compared to nDIAB patients might suggest a better anticancer effect of sorafenib in patients with diabetes. Also, the better TTP in DIAB treated with oral therapy as compared to those receiving insulin is interesting and concordant with previous studies on other cancer types. However, due to the retrospec-tive design of the analysis, these last findings need to be tested in prospective controlled studies.
Acknowledgments
Author Contributions • Study concept and design: GGDC, RT. • Acquisition of data: RT, GC, LF, LA.
• Analysis and interpretation of data: GGDC, FM, NC. • Drafting of the manuscript: GGDC, MG.
• Critical revision of the manuscript for important intellectual content: GGDC, MG, RT.
• Statistical analysis: GGDC. • Study supervision: GGDC.
All authors read and approved the final manuscript.
Compliance with Ethical Standards Funding None.
Conflict of Interest Giovan Giuseppe Di Costanzo, Raffaella Tortora, Filomena Morisco, Luigi Addario, Maria Guarino, Gabriella Cordone, Luigia Falco, and Nicola Caporaso declare no conflict of interest.
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